Cisplatin(cis-diamminedichloroplatinum("II"), CDDP) is a strong antitumor agent which is effective against many neoplasms. CDDP has improved the prognosis of patients having solid tumors including testicular, ovarian and non-small lung cell cancers. The cytotoxic effects of CDDP are thought to be due to attack on DNA bases and induction of apoptosis in cancer cells. In addition, the toxic effect of CDDP on renal tubular cells has also been shown to be due to the induction of apoptosis. The proportion of CDDP molecules available for attack on cancer cells and/or renal tubular cells in thought to be dependent on the serum unbound CDDP concentration or serum unbound CDDP fraction. Serum components such as albumin, hemoglobin, transferrin and -globulin were suggested to be the main ligands for CDDP and the binding of CDDP to albumin was considered to be essentially irreversible. To ascertain the reversible binding characteristics of CDDP, rat serum was used and both dialysis effeciency and
… More irreversible binding were measured in this study. These results suggest that both reversible and irreversible binding are involved in the binding of CDDP to rat serum. Furthermore, the effect of protein binding on the pharmacokinetics of cisplatin (CDDP) has also been studies in analbuminemic rats. However, there were not significant differences in the serum disappearance profiles of CDDP after iv bolus injection to analbuminemic rats as compared to normal rats. The serum BUN and creatinine levels at 6 hr after iv injection were higher in both groups of rats who received CDDP than the pre-dose level. However, there were not significant differences in these renal function tests between analbuminemic rats and normal rats. Higher binding percentages were obtained in analbuminenic rats than in normal rats. From these studies, it was elucidated that albumin is not the major ligand in the rat serum and that other proteins also have important role on the pharmacokinetics of CDDP.Moreover, the membrane transport studies using Caco-2 monolayer cell culture system showed that the more hydrophobid derivative carboplatin has higher membrane permeability than cisplatin. The apparent permeability constants of cisplatin and carboplatin were 0.0042±0.0041 ml/min/cmィイD12 ィエD1and 0.0077±0.0003 ml/min/cmィイD12ィエD1,respectively. Although, to characterize the membrane transport of cisplatin, several inhibitors for active transport system such as KCN and dinitrophenol etc. were spiked into the apical site, the active transport inhibitor could not show a clear inhibitory effect. Because the transported amount of cisplatin was extremely little. Less